1. Field of the Invention
The invention relates to 1.4-dihydropyridines which are radioactively labelled with .sup.35 S, to a process for their preparation and to their use for the testing of medicaments or other substances using radioreceptor assays and for the determination of the blood plasma levels of dihydropyridines.
2. Background Information
Calcium antagonists are defined as substances which block the passage of calcium through the calcium channels of the cell membrane. They are used therapeutically in the following areas, inter alia: angina pectoris, cardiac arhythmias, high blood pressure and vasospasm [D. J. Triggle, Calcium antagonists--Basic Chemical and Pharmacological Aspects, pages 1-18, in G. B. Weiss "New Perspectives on Calcium Antagonists", American Physiological Society, Bethesda, Maryland USA (1981)].
Calcium antagonists belong to various classes of chemical substances, the representatives of the 1,4-dihydropyridines being among the most effective since they block the passage of calcium through the calcium channels of the cell membrane of the smooth muscles even at low concentrations. This blockade is stereoselective in the case of chiral 1,4-dihydropyridines [A. Fleckenstein (1983), R. A. Janis and D. J. Triggle (1983), R. Towart, E. Wehinger, H. Meyer "Effects of unsymmetrical ester substituted 1,4-dihydropyridine derivatives and their optical isomeres on contraction of smooth muscle, Naunyn-Schmiedeberg's Arch. Pharmacol., 317, 183-5 (1981)].
In this connection, the use of dihydropyridines radioactively labelled with tritium or .sup.125 I for the characterization of binding sites of these drugs (receptors) has been described [H. Glossmann, D. R. Ferry, F. Lubbecke, R. Mews, F. Hoffmann, "Calcium channels--Direct identification with radioligand binding studies", TIPS, 3, 431-7, (1982); DE-OS (German Published Specification) No. 3,341,806].
Furthermore, 1,4-dihydropyridines labelled with tritium or .sup.125 iodine have been used for the blood plasma level determination of calcium antagonists and for the autoradiographic visualization of their receptors [R. Quirin, "Autoradiographic localization of a calcium channel antagonist-3H-nitrendipine, binding site in rat brain", Neuroscience Lett., 36, 267-71, (1983); DE-OS (German Published Specification) 3,341,806].
However, in view of the regulation on the disposal of radioactive wastes which is in force at present, substances which contain .sup.125 I, and especially .sup.3 H, are objectionable. Likewise, the radioactively labelled 1,4-dihydropyridines hitherto known frequently have only inadequate affinity and specificity for the corresponding receptors.
Hence, it was necessary to find radioactively labelled 1,4-dihydropyridines which are suitable for the testing of medicaments using radioreceptor assays, have a high specific and radiochemical stability, are straightforward to prepare, have a sufficiently short half-life, can be disposed of without difficulty and which, in particular, have high affinity and specificity for the 1,4-dihydropyridine receptors.